16-2118389-G-C

Variant names:

• chr16-2118389-G-C
• rs13334842
• NM_001009944.3:c.603C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001009944.3(PKD1):​c.603C>G​(p.His201Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000413 in 1,244,790 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H201H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (1 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.77
• Publications: 1 publications found

Genes affected

PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]

PKD1 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Caroli disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03233686).
• BP6: Variant 16-2118389-G-C is Benign according to our data. Variant chr16-2118389-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 997352.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.603C>G	p.His201Gln	missense	Exon 5 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.603C>G	p.His201Gln	missense	Exon 5 of 46	NP_000287.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.603C>G	p.His201Gln	missense	Exon 5 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.603C>G	p.His201Gln	missense	Exon 5 of 46	ENSP00000399501.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000351 AC: 47 AN: 133840 AF XY: 0.000302

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000551

Gnomad OTH exome AF: 0.000245

GnomAD4 exome AF: 0.000437 AC: 478 AN: 1092596 Hom.: 1 Cov.: 15 AF XY: 0.000368 AC XY: 203 AN XY: 551704

African (AFR) AF: 0.0000386 AC: 1 AN: 25904

American (AMR) AF: 0.000789 AC: 28 AN: 35466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23376

East Asian (EAS) AF: 0.00 AC: 0 AN: 34342

South Asian (SAS) AF: 0.00 AC: 0 AN: 73742

European-Finnish (FIN) AF: 0.0000298 AC: 1 AN: 33568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3510

European-Non Finnish (NFE) AF: 0.000521 AC: 424 AN: 814546

Other (OTH) AF: 0.000499 AC: 24 AN: 48142

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74410

African (AFR) AF: 0.00 AC: 0 AN: 41532

American (AMR) AF: 0.000850 AC: 13 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67972

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000175 Hom.: 1

Bravo AF: 0.000348

ExAC AF: 0.0000886 AC: 7

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	not specified (1)
-	-	1	PKD1-related disorder (1)
-	-	1	Polycystic kidney disease (1)
-	-	1	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.030
DANN	Benign	0.55
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-1.8
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.090
Sift	Benign	0.29	T
Sift4G	Benign	0.34	T
Polyphen		0.034	B
Vest4		0.12
MutPred		0.54		Gain of disorder (P = 0.0593)
MVP		0.76
ClinPred		0.071	T
GERP RS		-7.1
PromoterAI		0.037	Neutral
Varity_R		0.030
gMVP		0.44
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs13334842; hg19: chr16-2168390;